The invention relates to the treatment of hematologic disorders, e.g., disorders characterized by unwanted cells of hematopoietic origin, e.g., hematologic cancers.
Bone marrow transplantation (BMT) has yet to realize its full potential for the treatment of hematologic malignancies. The major obstacle to further advancement is graft-versus-host disease (GVHD), which is best be prevented by removing T cells from the donor marrow. Unfortunately, T cell-depletion has been associated with increased rates of engraftment failure (Martin, et al., Bone Marrow Transplant, 3:445-456 (1988)) and leukemic relapse (Butturini, et al., Bone Marrow Transplant, 3:265-279 (1988)). Despite improvements in pharmacologic GVHD prophylaxis, severe acute and chronic GVHD are still major complications of HLA-matched sibling bone marrow transplantation (Storb, et al., Blood, 73:1729-1734 (1989)) and (Sullivan, et al., Bone Marrow Transplantation: Current Controversies, 511 (1989)). Immunosuppressive drugs used for GVHD prophylaxis also increase the relapse rate for certain types of leukemia (Storb, et al., Blood, 73:1729-1734 (1989)); (Atkinson, et al., Aust. N. Z. J. Med., 4:587-593 (1989)); (Sullivan, et al., Blood, 73:1720-1728 (1989)); (Barrett, et al., Blood, 74:862-871 (1989)); and (Denham, et al., Br. J. Cancer, 47:791-795 (1983)). The subjects receiving allogeneic BMT are, nevertheless, a fortunate select group: most subjects do not have an HLA-matched sibling or a phenotypically-matched unrelated donor, and therefore do not have the option of BMT. Attempts to perform BMT between extensively HLA-mismatched donor-recipient pairs have been associated with a prohibitively high incidence of severe GVHD (Clift, et al., Ann. Rev. Immunol., 5:43-64 (1987)) and of failure of engraftment, a potentially lethal complication in myeloablated recipients (Anasetti, et al., New Engl. J. Med., 320:197-204 (1989)); (O'Reilly, et al., Transplantation. Proc., 17:455 (1985)); and (Fleischhauer, et al., New Engl. J. Med., 323:1818-1822 (1990)). Studies in animal models, however, have shown that MHC-disparate bone marrow transplants mediate anti-leukemic and anti-lymphoma effects that greatly exceed those achieved with MHC-matched BMT (Aizawa, et al., Transplantation, 52:885-889 (1991)); (Sykes, et al., Transplant. Proc., 21:3022-3024 (1989)). Clinical data also support the presence of increased graft-versus-leukemia/lymphoma (GVL) effects in the setting of HLA-mismatched BMT (Beatty, et al., Blood, 81:249-253 (1993)); (Drobyski, et al., Blood, 84:1980-1987 (1994)); (Sierra, et al., Blood, 89:4226-4235 (1997)), but this advantage has unfortunately been offset by a higher incidence of severe GVHD. Animal and clinical evidence for increased GVL effects occurring with the use of MHC-mismatched donors probably reflects the fact that the frequency of T cells in the unprimed repertoire that recognizes allogeneic MHC molecules is orders of magnitude greater than that recognizing any single non-MHC (minor or tumor-specific) antigen or multiple minor histoincompatibilities. Therefore, if the morbidity associated with GVHD and engraftment failure is avoided, the ability to perform HLA-mismatched BMT might be associated with GVL effects of sufficient magnitude to eradicate the most refractory hematologic malignancies. For example, subjects with chemo- and radio-resistant non-Hodgkins lymphomas (NHL) currently have few therapeutic options other than palliation. Results of closely-HLA-matched related allogeneic BMT have been disappointing, with durable remissions attained in 0-23% of subjects. Consequently, subjects with refractory NHL are not usually considered to be candidates for allogeneic BMT.
Many hematologic malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma, predominantly afflict older persons, in whom the increased risk of GVHD and other transplant-related complications rule out BMT as a therapeutic option. CLL is considered to be an incurable and ultimately fatal disease. Although promising results were achieved in a recent trial of allogeneic BMT in younger subjects with CLL (Rabinowe, et al., Blood, 82:1366-1376 (1993)), BMT has not been widely used for this leukemia, despite the fact that there are no known curative therapies to offer this group of subjects. Therefore, there is a continuing need to reduce the risk of GVHD in BMT immunocompetent subjects and to develop curative therapies for adult, immunocompetent subjects suffering from hematologic or lymphohematologic disorders, such as refractory, aggressive NHL.